The design, synthesis and biological evaluations of C-6 or C-7 substituted 2-hydroxyisoquinoline-1,3-diones as inhibitors of hepatitis C virus

Yue Lei Chen, Jing Tang, Matthew J. Kesler, Yuk Y. Sham, Robert Vince, Robert J. Geraghty, Zhengqiang Wang

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

C7-Substituted 2-hydroxyisoquinoline-1,3-diones inhibit the strand transfer of HIV integrase (IN) and the reverse-transcriptase-associated ribonuclease H (RNH). Hepatitis C virus (HCV) NS5B polymerase shares a similar active site fold to RNH and IN, suggesting that N-hydroxyimides could be useful inhibitor scaffolds of HCV via targeting the NS5B. Herein we describe the design, chemical synthesis, replicon and biochemical assays, and molecular docking of C-6 or C-7 aryl substituted 2-hydroxyisoquinoline-1,3-diones as novel HCV inhibitors. The synthesis involved an improved and clean cyclization method, which allowed the convenient preparation of various analogs. Biological studies revealed that the C-6 analogs, a previously unknown chemotype, consistently inhibit both HCV replicon and recombinant NS5B at low micromolar range. Molecular modeling studies suggest that these inhibitors may bind to the NS5B active site.

Original languageEnglish (US)
Pages (from-to)467-479
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number1
DOIs
StatePublished - Jan 1 2012

Keywords

  • 2-Hydroxyisoquinoline-1,3-dione
  • Hepatitis C virus (HCV)
  • NS5B polymerase

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